Redox mechanisms of muscle dysfunction in inflammatory disease

Oxidative stress is a major component of the pathology that affects striated muscle in a wide variety of inflammatory diseases. Under these conditions, muscle-derived ROS exceed the local buffering capacity of tissue antioxidants; this perturbs the regulation of contractile function and gene expression, leading to loss of function via two parallel and largely independent mechanisms. The underlying biology can be illustrated using four different pathologic settings. First, in cachexia, elevated levels of circulating cytokines (notably TNF-α and IL-1B) act via receptor-mediated mechanisms to stimulate ROS production within muscle fibers. The resulting increase in ROS levels activates redox-sensitive signal transduction pathways that involve NF-κB and p38 MAPK as essential elements. These signaling events increase mRNA levels for muscle-specific E2 and E3 proteins, elevating the general rate of ubiquitin conjugation. This elevation results in loss of structural proteins and overt muscle atrophy. Second, ROS modulate growth and repair of skeletal and cardiac muscles in response to humoral mediators, including Ang II. Studies of cellular mechanisms indicate that growth-related pathways, particularly the Ras/Raf and PI3K/Akt/mTOR pathways, are redox sensitive and can be activated by ROS that function as second messengers. Third, studies have identified intermittent hypoxia as a novel stimulus for oxidative stress in the clinical setting of SDB. This is a persistent problem in individuals with chronic sleep apnea. It can lead to hypertension, cardiac hypertrophy, and decrements in cardiac function via mechanisms that remain poorly understood. New experimental approaches are being used to dissociate the components of this pathology and identify the physiologic mechanisms of oxidant effects on the heart. Fourth, heart failure provides a clinical example of ROS-mediated contractile dysfunction that can develop in skeletal muscle without overt atrophy or injury. Loss of function seems to reflect redox modulation of regulatory proteins within muscle fibers, components of either the myofilament lattice (myosin heavy chains, troponin C, actin) or the sarcoplasmic reticulum complex (ryanodine-sensitive calcium release channel, calcium-dependent ATPase). In these and other inflammatory pathologies, muscle-derived ROS and the antioxidant interventions used to study ROS actions can have complex, apparently divergent effects. The authors approach the problem in the context of redox homeostasis, viewing muscle-derived ROS as physiologic components of the cellular milieu and inflammatory mediators as perturbing stimuli. This context provides a useful model for interpreting existing data and for identifying new directions of experimental research.